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Molecular investigation of genetic factors associated with insulin resistance and obesity in a South African population

Vergotine, Zelda (2015-12)

Thesis (PhD)--Stellenbosch University, 2015.

Thesis

ENGLISH ABSTRACT: Background: The aetiopathogenesis of type 2 diabetes and the associated insulin resistance have
been shown to have a strong genetic basis. Several genetic variants of the peroxisome proliferatoractivated
receptor gamma (PPARG) and the insulin receptor substrate (IRS) 1 genes have been
associated with the metabolic states of obesity, insulin resistance and type 2 diabetes in Caucasian
populations. Furthermore, insulin resistance is strongly associated with diabetes and subsequent
cardiovascular disease. These are increasingly common in low- to middle -income countries,
including South Africa. Limited information is currently available regarding genetic associations
with insulin resistance in African populations.
Objectives: (1) To identify subjects with insulin resistance and determine the frequencies of the
single nucleotide polymorphisms in the PPARG and IRS1 genes and examine the associated risk of
insulin resistance and type 2 diabetes mellitus in a mixed-ancestry South African population. (2) To
investigate the relationship between indices of insulin resistance and carotid intima media
thickness, a marker of subclinical cardiovascular disease/atherosclerosis. Methods: A total of 856 (235 males) mixed-ancestry adults drawn from an urban community of
Bellville South, Cape Town were genotyped for PPARG Pro12Ala (rs1801282, G>C), Pro115Gln
(rs1800571, G>T), Val290Met (rs72551362, G>A), Pheu388Leu (rs72551363, T>A), Arg397Cys
(rs72551364, C>T), His449His (rs3856806, C>T) and IRS1 Gly972Arg (rs 1801278, G>A). The
oral glucose tolerance test was performed and cardiometabolic risk factors measured. Insulin
resistance was estimated by the homeostasis model assessment of insulin resistance, the
homeostasis model assessment of functional beta-cells, the quantitative insulin-sensitivity check
index, the fasting insulin resistance index and the glucose/insulin ratio. Carotid intima media
thickness was measured in longitudinal section at the far wall of the distal common carotid arteries,
2 cm from the bifurcation, at three consecutive end-points, 5-10 mm apart. Results: The genotype frequencies of PPARG Pro12Ala, IRS1 Gly972Arg and PPARG His449His
were 10,4%, 7,7% and 23,8% respectively. No mutations were found for PPARG Pro115Gln,
Val290Met, Pheu388Leu and Arg379Cys. In a model containing both PPARG Pro12Ala and
IRS1 Gly972Arg alleles and their interaction term, the presence of the PPARG Pro12 resulted in a
64% risk of prevalent type 2 diabetes mellitus and was associated with higher 2 hour post-OGTT
insulin levels in subjects with normoglycaemia. The PPARG Pro12 was associated with insulin
resistance and interacted with IRS1 Gly972Arg, increasing the risk of type 2 diabetes mellitus. The
PPARG His449His allele T frequency was about 14% and in an additive genetic model significantly
reduced the risk of diabetes by 44%. After adjustment for age, gender, body mass index and
diabetes status, the fasting plasma glucose (β=0,087;p=0,042) and glucose/insulin ratio
(β=0,026; p=0,026) were associated with carotid intima media thickness. However, the effect on
the overall model performance was marginal, R2<29,7%. Conclusion: The PPARG Pro12 was associated with insulin resistance and showed a gene-gene
interaction with the unfavorable polymorphism IRS1 Gly972Arg, leading to an increased risk of
type 2 diabetes mellitus. In contrast, the PPARG His449His T allele showed a protective effect
against the risk of developing diabetes. Furthermore, indices of insulin resistance such as
homeostatis model assessment of insulin resistance, quantitative insulin-sensitivity check index,
fasting insulin resistance index and the glucose/insulin ratio were weakly associated with carotid
intima media thickness in the risk stratification of cardiovascular disease in this population.